Enalapril reduces the albuminuria of patients with sickle cell disease

1m

CLINICAL

STUDIES

Enalapril Reduces the Albuminuria With Sickle Cell Disease

of Patients

Regina Y. Aoki, MD, Sara T.O. Saad, MD, Campinas, Brazil

PURPOSE: To evaluate the effects Of t?tIaiaprii, an angiotensin-converting enzyme inhibitor, on albuminuria associated with sickle cell anemia. PATIENTS AND METHODS: Two males and 6 females, mean age 22.8 e 5.5 years, with sickle cell anemia and albuminuria, received enalapril for 6 months. Before entry into the study, all had a urinary albumin concentration above 30 mg,/L as determined by radioimmunoassay documented on three separate occasions at intervals of 15 to 30 days. Samples were collected before 10 AM after an oral water load of 10 ml/kg. RESULTS: Enalapril reduced 6 patients’ pretreatment hyperalbuminuria to normal. One patient whose levels did not reach normal values experienced a reduction of 70%. Fractional excretion of sodium, potassium, and lithium did not change during the treatment. Mean arterial pressure decreased by 8.6 f 0.42 mm Hg. Two years after enalapril was discontinued, there were no changes in sodium, potassium, or creatinine levels of 7 patients who had received enalapril or in their mean arterial pressures. Urinary albumin concentration increased relative to pretreatment levels in 2 individuals, returned to pretreatment levels in 2, and remained below 30 mg/L in 2. CONCLUSION: Our results demonstrate that enalapril reduces albuminuria in patients with sickle cell anemia. After discontinuation of the drug, however, the albuminuria may increase to pretreatment levels or higher. Whether the reduction in urinary albumin concentration by angiotensin-converting enzyme inhibitors can delay the development of progressive renal failure in sickle cell anemia patients remains to be established.

F

ocal segmental glomerulosclerosis in the setting of glomerular hypertrophy is a common lesion in sickle cell disea.se.ld One explanation for this glomerular hypertrophy is a vasodilation of the afFrom the Hematology Division, Department of Internal Medicine and Hemocentro, State Universi?, of Campinas, Campinas-SP, Brazil.

ferent glomerular arterioles and glomerular hypertension resulting from the increased renal production of prostaglandins by the kidney.5 Thus, young patients with sickle cell disease have supranormal renal hemodynamics with an elevated glomeruh f&ration rate and renal plasma flo~.~ The prolonged glomerular hyperfiltration may damage the glomeruli, leading to glomerular sclerosis, proteinuria, and progressive renal failure.g The prevalence of proteinuria in patients with sickle cell disease has varied from 17% to 33% in several studies in which protemuria was determined by the dipstick method.‘JOJ1 While asymptomatic and relatively common, proteinuria is associated with reduced creatinine clearance in patients over 40 years old with sickle cell anemia.l” Angiotensin-converting enzyme (ACE) inhibitors preferentially dilate the efferent glomerular arterioles, leading to a fall in the intraglomerular pressure and a decrease in the glomerular permeability to albumin.13 These drugs are able to reduce albuminuria in normotensive patients with incipient diabetic nephropathy14> l5 as well as proteinuria in patients with renal disease of various origins.16 Falk et al’ administered enalapril for 2 weeks to sickle cell anemia patients and observed a 57% decrease in their mean 24hour urinary protein excretion. Healthy adults excrete from 2 to 26 mg of albumin daily in their urine, with a geometric mean of 9.5 mg/d.17 Albumin comprises up to 11% of their total urinary protein. These levels are defined as normoalbuminuria. Urinary albumin excretion can vary due to the combined effects of concentration, urine flow, and inherent day-to-day variability. Day-to-day variability is generally around 40% and decreases when the samples are collected early in the morning. Although hydration status fluctuates, the intraindividual variance is lower for albumin concentration than for albumin excretion rate. l8 Forty percent of teenagers and adults with sickle cell anemia present abnormal albuminuria. l8 The aim of this study was to evaluate whether or not the ACE inhibitor enalapril is able to lower the albuminuria in patients with sickle cell anemia and, if so, for how long.

PATIENTS AND METHODS Manuscript

432

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submitted August 19, 1993 and accepted in revised form

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Eight patients with sickle cell anemia and albuminuria received enalapril. They were 2 males and 6 98

ENALAPRIL

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STATISTICAL ANALYSIS Significance was defined as P ~0.05. Variations in albuminurla, mean arterial pressure, creatinine clearance, serum potassium, and fractional excretion of sodium and potassium were compared by regression analysis. To compare fractional excretion of lithium before and after 6 months of enalapril treatment, we used the Wilcoxon signed rank test. To compare patients and controls we used the Mann-Whitney U test.

RESULTS

a

30

so

@a TIME

120

1w

lw

FOLLOW

= UP

(DAYS)

Figure. Urinary albumin concentration (mg/L) in patients with sickle cell anemia before (0 days) and during enalapril treatment (30, 60, 90, 120, 150, 180 days) and 2 years after discontinuation of the drug (follow-up]. Shaded area corresponds to the normal range.

females with a mean age of 22.8 f: 5.5 years. All were clinically stable and the diagnosis of sickle cell disease was based on clinical, familial, and laboratory data, including electrophoresis on cellulose acetate at pH 8.9 and on agar gel at pH 6.2,“O the solubility test,” and the estimation of HbF2 and Hl~42.~~ All gave informed consent. The study was approved by the Ethical Committee of this hospital. Our eligibility criteria required urinary albumin concentration (UAC) above 30 mg/L on three separate occasions at, intervals of 15 to 30 days. Ten normal individuals (5 males, 5 females; mean age 29.6 + 4.5 years) had mean UAC levels of 9.55 2 5.22 mg/l,. Samples were collected before 10 AM following an oral water load of 10 mL%g. Albumin was measured by radioimmunoassay (Kit Pharmacia, Uppsala, Sweden). None of the patients had hypertension or serum creatinine levels higher than 1.7 mg/dL. After three pretreatment determinations of arterial pressure, UAC, serum and urinary electrolytes, and creatinine clearance, the patients took oral enalapri15 mg daily for 6 months. All measurements were repeated every 15 to 30 days. Lithium ctearance was performed before and after the treatment, as previously described.2”J” After 2 years without enalapril, we repeated the UAC determination. Blood pressure was measured with a standard mercury sphygmomanomet,er. Mean arterial pressure (MAP) was calculated as the diastolic blood pressure plus one third of the difference between systolic and diastolic pressure. Sodium, potassium, and lithium were measured by flame spectrophotometry and creatinine by the Jaff6 reaction.

Pretreatment hyperalbuminuria decreased to normal in 6 patients (Figure). One patient whose levels did not reach normal values experienced a 70% reduction. In one patient the change in albuminuria was not measured because the values were above the limit of detection of the method used. There were no adverse effects from enalapril treatment and no vase-occlusive crises. Before enalapril treatment, the creatinine clearance was higher in patients than controls (P = O.OOS), and the mean arterial pressure and fractional excretion of potassium and lithium were significantly lower (P = 0.002,P = 0.014, and P = 0.001, respectively). These values did not change significantly during the course of treatment except for the decrease in the MAP. There was a tendency to increase. the serum potassium levels during the course of treatment. These results are presented in the Table. Two years after enalapril was discontinued, we repeated all measurements in 6 patients who had received the drug and in 2 sickle cell anemia patients who presented UAC above 30 mg/L but did not participate in the study. There were no changes in sodium, potassium, and creatinine levels or in the mean arterial pressure. Urinary albumin concentration increased in all individuals, except, for 4 patients who had received enalapril. The UAC returned to pretreatment levels in 2. The other 2 still had values below 30 mg/L (Figure).

DISCUSSION Our results demonstrate that enalapril reduces albumintia in patients with sickle cell anemia. After discontinuation of the drug the albuminuria may increase to pretreatment levels or higher. Enalapril did not alter creatinine clearance or sodium, potassium, or lithium fractional excretion. Arterial pressure decreased with enalapril. Although this reduction in blood pressure could partially account for the fall in albuminuria, our results suggest the presence of a more specific antiprotelnuric effect of ACE inhibitors. Such an effect would explain the results in 2 patients whose albuminuria decreased markedly with only mild reductions in blood pressure, and whose low albuminuria values persisted while their blood pes May

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ENALAPRK IN SICKLE CELL DISEASE/AOKl AND SAAD TABLE Clinical and Laboratory Data (Mean f SD) for Patients With Sickle Cell Anemia Before and During Enalapril Treatment and 2 Years After Discontinuation of the Drug (Follow-Up) Sickle Cell Anemia Patients (n = 8) Enalapril Treatment Controls After 6 Months Before (n = 10) MAP (mm Hg) KS (mEq/LI FEK (%) FELi (%I FENa (%I CreatCl (ml/mid

86.9 + 8.6 4.5 + 0.2 4.2 k 1.1 28.8 + 9.1 0.9 zk0.2 109 + 19

70.4 * 5.5+ 5.0 f 0.6 2.1 i: 1.0’ 10.9 + 6.165 0.7 rl 0.2

175 * 46

178 * 58i

‘Significantly lower (P = 0.004) when compared to before or follow-up values. tf = 0.002 vs. controls. $P = 0.014 vs. controls. §P = 0.001 vs. controls. Significantly different when compared to controls. MAP = mean arterial pressure; KS = serum potassium; FEK = fractional excretion of potassium; excretion of sodium CreatCl = creatinine clearance.

sures returned to baseline levels after discontinuation

of the drug. The elevated creatinine clearance observed in this study is a common finding and probably reflects the high creatinine secretion in the proximal tubules and the supranormal renal hemodynamics that are both usually found in sickle cell anemia patientsx An apparent hyperkalemia is usually observed in sickle cell disease and may be artifactual because of the tendency of HbS-containing cells to release potassium on standing. 2SAfter enalapril was discontinued, these biochemical parameters maintained their baseline values. In sickle cell anemia, the proximal tubule is hyperfUnctional,“” as was confiied by the low fractional excretion of lithium observed in our study. Throughout enalapril treatment, this laboratory parameter remained unchanged or tended to normalize. ACE inhibitors induce renal vasodilation. In healthy volunteers and in patients with essential hypertension and normal renal function, both captopril and enalapril stimulate a rise in the effective renal plasma flo~.““:~~ Efferent vascular tone Cpostglomerular) is regulated primarily by angiotensin II W9 hence efferent vasomotor tone will decrease aft& ACE inhibition.‘” The reduction in proteinuria is most likely related to decreased renal vascular resistance, particularly in postglomerular arterioles, which results in a fall in the intraglomerular capillary pressure. In the rat renal ablation model,“0 the development of glomerulosclerosis and progressive albuminuria can be prevented by normalizing glomerular capillary pressure through the use of ACE inhibitors. Renal protection by ACE inhibitors has been described in hypertensive and normotensive patients with diabetic nephropathf”-“S and also in nondiabetic patients with proteinuria. :WXIn addition, a long-term (5 years) stabilizing effect of ACE inhibitors on 434

61.7 + 3.4’ 5.5 f 1.0 2.1 + 0.7 21.1 k 16.3 0.6 f 0.3

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FELi = fractional excretion

Follow-Up

72.2 + 6.9 5.2 t 0.8 2.2 * 1.0 0.7 * 0.3 180 + 50

of lithium; FENa = fracttonal

plasma creatinine and on proteinuria in normotensive type II diabetic patients has been reported.36 Whether the decrease in the urinary albumin concentration by enalapril treatment delays the course of progressive renal failure in sickle cell anemia patients remains to be established.

ACKNOWLEDGMENT We are most grateful to Drs. Mario J.A. Saad, Waldir Eduardo Garcia, and Fernando F. Costa for helpful discussions. We also thank Drs. Stephen Hyslop and Mary Lucy S. Queiroz for proofreading the manuscript.

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